BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

Objective:To observe and analyze thyroxine levels in children with retinopathy of prematurity (ROP) and its effect on severe ROP.Methods:A retrospective clinical study. From January 2022 to December 2023, a total of 64 premature infants with severe ROP (ROP group), hospitalized in the Children's Hospital Affiliated to Zhengzhou University and with a gestational age ≤32 weeks, were included. According to a 1:2 ratio, 128 premature infants without ROP, matched for sex and gestational age, were selected as the control group. Thyroid function tests were performed 7 to 14 d after birth. The levels of thyroid-stimulating hormone, triiodothyronine, free triiodothyronine, thyroxine (T4), and free T4 (FT4) were compared and observed between the two groups. The quantitative data between groups were compared by independent samples t-test or Mann-Whitney U test; the count data were compared by χ2 test. Logistic regression was used to analyze the correlation between various variables and the occurrence of severe ROP. The predictive efficacy of the differential indicators was assessed by receiver operating characteristic (ROC) curve. Results:Compared with the control group, T4 and FT4 levels were significantly lower in children in the ROP group, and the difference was statistically significant ( t=2.572, 2.704; P=0.011, 0.008). The results of univariate logistic regression analysis showed that the Apgar scores at 1 and 5 minutes, as well as sepsis, T4, FT4, and bronchopulmonary dysplasia (BPD), were significantly associated with the occurrence of severe ROP ( P<0.05). The results of multivariate logistic regression analysis indicated that FT4 and BPD are independent risk factors for the occurrence of severe ROP ( P<0.05). The ROC curve analysis revealed that T4 had a sensitivity of 80.9% and specificity of 43.3%, while FT4 showed a sensitivity of 46.8% and specificity of 75.0%, with abnormal cutoff values set at 98.4 nmol/L for T4 and 15.65 pmol/L for FT4. Conclusions:The T4 and FT4 level of children with severe ROP are lower than that of children without ROP in the early postnatal period. The T4 and FT4 level in the early postnatal period may have a certain correlation with the occurrence of severe ROP.

OBJECTIVE To analyze the comprehensive intervention measures to raise the etiological submission rate for hospitalized patients before antimicrobial treatment and evaluate the effect.METHODS The hospitalized pa-tients who were treated with therapeutic antibiotics in the Affiliated Hospital of Inner Mongolia Medical University from Jan.2023 to Jun.2023 were assigned as the exploratory analysis phase,the hospitalized patients who were treated with therapeutic antibiotics from Jul.2023 to Dec.2023 were assigned as the first post-intervention phase,and the hospitalized patients who were treated with therapeutic antibiotics from Jan.2024 to Mar.2024 were as-signed as the second post-intervention phase.The related indexes for etiological submission rate before the antimi-crobial treatment were compared before and after the intervention.RESULTS After the comprehensive interven-tion,the etiological submission rate of the entire hospital before the antimicrobial treatment was increased from 28.30％to 42.22％in the first post-intervention phase and 55.86％in the second post-intervention phase.The etio-logical submission rate with respect to diagnosis of hospital-associated infection was increased from 68.34％before the intervention to 85.85％in the first post-intervention phase and 94.58％in the second post-intervention phase.The incidence of hospital-associated infection showed a slight downward trend,dropping from 1.51％to 1.27％in the first post-intervention phase and 1.11％in the second post-intervention phase.The proportion of submission of sterile samples showed a slight upward trend,which was 26.13％before the intervention,29.57％in the first post-intervention phase,28.96％in the second post-intervention phase.There were significant differences in the a-bove indexes(P＜0.05).The etiological submission rate before the combined use of key drugs was increased from 84.71％to 85.95％in the first post-intervention phase and 88.33％in the second post-intervention phase,and there was no significant difference.CONCLUSIONS The etiological submission rate of the hospitalized patients be-fore the antimicrobial treatment is remarkably raised by taking the comprehensive intervention measures,but the etiological submission rate before the combined use of key drugs does not meet the standard,the proportion of submission of the sterile samples is not remarkably raised.It is necessary to continuously complete the intervention measures in the next phase.

Objective:The study investigated the full-time Clinical Research Coordinators (CRCs) working in hospitals on their current working situation and explored affecting factors to provide suggestions for a professional and systemic clinical research workforce establishment in municipal medical institutions.Methods:A questionnaire survey was designed for CRCs in municipal hospitals in Shanghai, descriptive and one-way cross-tabulation analysis were conducted, using t-test for continuous numerical variables, rank-sum test for count variables and chi-square test for categorical variables.Results:Totaling 177 CRCs in 9 municipal hospitals in Shanghai answered the questionnaire. The average age of the respondents was 28.56±7.299 years old. Their professional background was mainly nursing and pharmacy (139/177, 87.53%), and bachelor degree (114/177, 64.41%). Averagely worked 2.50±1.632 years, the average number of research projects undertaken by CRC was 3.45±2.179, and the average number of cumulative projects involved was 8.72±9.341. The CRCs employed by hospitals mainly undertook Investigator-Initiated clinical Trial/Research projects (IITs) (26/36, 72.22%), while the CRCs employed by SMO companies mainly undertook Industry-Sponsored Clinical Trial (IST) projects (96/141, 68.09%). 85.88% (152/117) of CRCs held GCP certificates valid within three years, and the proportion of CRCs employed by hospitals held GCP certificates was lower than that of SMO companies ( P<0.05). Among the CRCs employed by hospitals, 23 (63.89%) said they had no position or were not clear about their position; The CRCs in SMO companies were mainly primary and intermediate (χ 2=84.119, P<0.05). The average number of research projects undertaken by CRC was 3.45±2.179, and the average number of cumulative projects involved was 8.72±9.341. Conclusions:With the development of clinical research, the full-time specialized CRCs in medical institutions mainly have 2 sources: from SMO/CRO companies or self-employment by medical institutions. In general, there are still problems in the CRC talent team as unclear entry standards, insufficient, lack career positioning planning, large mobility, imperfect training system, and imperfect promotion mechanism. It is suggested to unify occupational access standards and set specialty in colleges or universities. Strengthen post-service education and training system, establish multi-party collaborative training mechanism, standardize the assessment and evaluation, improve the job title promotion system, to promote the rapid development of CRC team.

OBJECTIVE To analyze the comprehensive intervention measures to raise the etiological submission rate for hospitalized patients before antimicrobial treatment and evaluate the effect.METHODS The hospitalized pa-tients who were treated with therapeutic antibiotics in the Affiliated Hospital of Inner Mongolia Medical University from Jan.2023 to Jun.2023 were assigned as the exploratory analysis phase,the hospitalized patients who were treated with therapeutic antibiotics from Jul.2023 to Dec.2023 were assigned as the first post-intervention phase,and the hospitalized patients who were treated with therapeutic antibiotics from Jan.2024 to Mar.2024 were as-signed as the second post-intervention phase.The related indexes for etiological submission rate before the antimi-crobial treatment were compared before and after the intervention.RESULTS After the comprehensive interven-tion,the etiological submission rate of the entire hospital before the antimicrobial treatment was increased from 28.30％to 42.22％in the first post-intervention phase and 55.86％in the second post-intervention phase.The etio-logical submission rate with respect to diagnosis of hospital-associated infection was increased from 68.34％before the intervention to 85.85％in the first post-intervention phase and 94.58％in the second post-intervention phase.The incidence of hospital-associated infection showed a slight downward trend,dropping from 1.51％to 1.27％in the first post-intervention phase and 1.11％in the second post-intervention phase.The proportion of submission of sterile samples showed a slight upward trend,which was 26.13％before the intervention,29.57％in the first post-intervention phase,28.96％in the second post-intervention phase.There were significant differences in the a-bove indexes(P＜0.05).The etiological submission rate before the combined use of key drugs was increased from 84.71％to 85.95％in the first post-intervention phase and 88.33％in the second post-intervention phase,and there was no significant difference.CONCLUSIONS The etiological submission rate of the hospitalized patients be-fore the antimicrobial treatment is remarkably raised by taking the comprehensive intervention measures,but the etiological submission rate before the combined use of key drugs does not meet the standard,the proportion of submission of the sterile samples is not remarkably raised.It is necessary to continuously complete the intervention measures in the next phase.

Objective:The study investigated the full-time Clinical Research Coordinators (CRCs) working in hospitals on their current working situation and explored affecting factors to provide suggestions for a professional and systemic clinical research workforce establishment in municipal medical institutions.Methods:A questionnaire survey was designed for CRCs in municipal hospitals in Shanghai, descriptive and one-way cross-tabulation analysis were conducted, using t-test for continuous numerical variables, rank-sum test for count variables and chi-square test for categorical variables.Results:Totaling 177 CRCs in 9 municipal hospitals in Shanghai answered the questionnaire. The average age of the respondents was 28.56±7.299 years old. Their professional background was mainly nursing and pharmacy (139/177, 87.53%), and bachelor degree (114/177, 64.41%). Averagely worked 2.50±1.632 years, the average number of research projects undertaken by CRC was 3.45±2.179, and the average number of cumulative projects involved was 8.72±9.341. The CRCs employed by hospitals mainly undertook Investigator-Initiated clinical Trial/Research projects (IITs) (26/36, 72.22%), while the CRCs employed by SMO companies mainly undertook Industry-Sponsored Clinical Trial (IST) projects (96/141, 68.09%). 85.88% (152/117) of CRCs held GCP certificates valid within three years, and the proportion of CRCs employed by hospitals held GCP certificates was lower than that of SMO companies ( P<0.05). Among the CRCs employed by hospitals, 23 (63.89%) said they had no position or were not clear about their position; The CRCs in SMO companies were mainly primary and intermediate (χ 2=84.119, P<0.05). The average number of research projects undertaken by CRC was 3.45±2.179, and the average number of cumulative projects involved was 8.72±9.341. Conclusions:With the development of clinical research, the full-time specialized CRCs in medical institutions mainly have 2 sources: from SMO/CRO companies or self-employment by medical institutions. In general, there are still problems in the CRC talent team as unclear entry standards, insufficient, lack career positioning planning, large mobility, imperfect training system, and imperfect promotion mechanism. It is suggested to unify occupational access standards and set specialty in colleges or universities. Strengthen post-service education and training system, establish multi-party collaborative training mechanism, standardize the assessment and evaluation, improve the job title promotion system, to promote the rapid development of CRC team.

Objective:To observe and analyze thyroxine levels in children with retinopathy of prematurity (ROP) and its effect on severe ROP.Methods:A retrospective clinical study. From January 2022 to December 2023, a total of 64 premature infants with severe ROP (ROP group), hospitalized in the Children's Hospital Affiliated to Zhengzhou University and with a gestational age ≤32 weeks, were included. According to a 1:2 ratio, 128 premature infants without ROP, matched for sex and gestational age, were selected as the control group. Thyroid function tests were performed 7 to 14 d after birth. The levels of thyroid-stimulating hormone, triiodothyronine, free triiodothyronine, thyroxine (T4), and free T4 (FT4) were compared and observed between the two groups. The quantitative data between groups were compared by independent samples t-test or Mann-Whitney U test; the count data were compared by χ2 test. Logistic regression was used to analyze the correlation between various variables and the occurrence of severe ROP. The predictive efficacy of the differential indicators was assessed by receiver operating characteristic (ROC) curve. Results:Compared with the control group, T4 and FT4 levels were significantly lower in children in the ROP group, and the difference was statistically significant ( t=2.572, 2.704; P=0.011, 0.008). The results of univariate logistic regression analysis showed that the Apgar scores at 1 and 5 minutes, as well as sepsis, T4, FT4, and bronchopulmonary dysplasia (BPD), were significantly associated with the occurrence of severe ROP ( P<0.05). The results of multivariate logistic regression analysis indicated that FT4 and BPD are independent risk factors for the occurrence of severe ROP ( P<0.05). The ROC curve analysis revealed that T4 had a sensitivity of 80.9% and specificity of 43.3%, while FT4 showed a sensitivity of 46.8% and specificity of 75.0%, with abnormal cutoff values set at 98.4 nmol/L for T4 and 15.65 pmol/L for FT4. Conclusions:The T4 and FT4 level of children with severe ROP are lower than that of children without ROP in the early postnatal period. The T4 and FT4 level in the early postnatal period may have a certain correlation with the occurrence of severe ROP.

ObjectiveTo investigate the antidepressant effect of Sinisan （SNS） by regulating glycogen aynthase kinase-3β （GSK-3β）/tumor necrosis factor alpha-induced protein 3（A20）/CCAAT enhancer binding protein β（C/EBPβ） to inhibit the activation of microglia. MethodA total of 72 male C57/6J mice were randomly divided into the normal group， model group， fluoxetine group （5.0 mg·kg^-1）， low-dose Sinisan group （4.9 g·kg^-1）， medium-dose Sinisan group （9.8 g·kg^-1）， and high-dose Sinisan group （19.6 g·kg^-1）， with 12 mice in each group. After one week of adaptive feeding， chronic unpredictable mild stress （CUMS） was performed to establish the depression model. In the fifth week， drug treatment was conducted for four weeks. In the ninth week， behavioral tests were performed， including sucrose preference test （SPT）， open field test （OPT）， elevated plus maze （EPM） test， and forced swimming test （FST）. Western blot was used to detect the expression levels of interleukin-1β （IL-1β）， interleukin-6 （IL-6）， nitric oxide synthase （iNOS）， GSK-3β， A20， and C/EBPβ in the cortex. The expression of M1-polarized ionized calcium-binding adapter molecule 1 （Iba1） and cluster of differentiation 68 （CD68） in microglia was detected by immunofluorescence. ResultAfter eight weeks of CUMS， compared with the normal group， the mice in the model group had a significantly reduced sucrose preference rate （P<0.01）， and the activity in the central area of the OPT was significantly reduced （P<0.01）. The activity in the open arm area of the EPM test was significantly reduced （P<0.05）， and the immobility time of FST was increased （P<0.01）. The expression levels of inflammatory proteins IL-1β， IL-6， and iNOS were increased （P<0.01）， and the fluorescence co-localization index of Iba1 and CD68 was increased （P<0.05）. The protein expression levels of GSK-3β and C/EBPβ were significantly increased （P<0.05， P<0.01）. After four weeks of SNS intervention， compared with the model group， the mice in the SNS group had significantly increased sucrose preference rate （P<0.01）， significantly increased activities in the central area and the open arm area in the OPT and the EPM test （P<0.05）， and significantly reduced immobility time in the FST （P< 0.01）. The protein expression levels of IL-1β， IL-6， and iNOS were significantly decreased （P<0.05）， and the fluorescence co-localization index of Iba1 and CD68 was decreased in the high-dose SNS group （P<0.05）. The protein expression levels of GSK-3β and C/EBPβ in the medium-dose and high-dose SNS groups were significantly decreased （P<0.01）， and that of A20 was significantly increased （P<0.01）. ConclusionThe antidepressant effect of SNS is related to the regulation of GSK-3β/A20/C/EBPβ protein expression and the inhibition of M1-type activation of microglia.

The Chinese Neonatal Network(CHNN) was established in 2018 with the mission of establishing a national collaboration platform, conducting high-quality and collaborative research, and ultimately improving the quality of neonatal-perinatal care and health in China.At present, 112 hospitals across the country have joined CHNN.CHNN has established a national standardized cohort of very premature infants/very low birth weight infants with >10 000 enrollments each year, has been leading data-driven collaborative quality improvement initiatives, conducting multicenter clinical studies, and performing multi-level training programs.Guided by the principles of collaboration and sharing, data-driven, continuous improvement, and international integration, CHNN has become an important platform for clinical and research collaboration in neonatal medicine in China.

Objective:To investigate the 2 years’ efficacy of intravesical instillation of domestic BCG versus epirubicin in the prevention of recurrence of intermediate-risk or high-risk non-muscular invasive bladder cancer and predictive factors of BCG instillation.Methods:From July 2015 to June 2020, 18-75 years old patients with moderate to high-risk non muscle invasive bladder cancer (NMIBC) confirmed by pathological examination were involved. The ECOG score was 0-2. Exclusion criteria included ①immune deficiency or impairment (such as AIDS), using immunosuppressive drugs or radiotherapy, suspected allergic to BCG or epirubicin or excipients of the two drugs, fever or acute infectious diseases including active tuberculosis or receiving anti tuberculosis treatment, with severe chronic cardiovascular and cerebrovascular diseases or chronic kidney disease; ②combined with other urogenital system tumors or other organ tumors; ③combined with muscle invasive bladder urothelial carcinoma (≥T 2); ④undergoing chemotherapy, radiotherapy or immunotherapy within 4 weeks (immediate instillation after surgery not included); ⑤ pregnant or lactating women; ⑥ comfirmed or suspected bladder perforation; ⑦gross hematuria; ⑧cystitis with severe bladder irritation that may affect the evaluation; ⑨participat in other clinical trials within 3 months; ⑩alcohol or drug addiction; ?any risk factors that may increasing the risk of patients. Epirubicin 50 mg was irrigated immediately after the operation(TURBT or laser resection). The patients were randomly divided into BCG15 group, BCG19 group and epirubicin group by the ratio of 2∶2∶1, and the patients were maintained intravescical instillation for 1 year. The recurrence and adverse events of the three groups were compared. Univariate and multivariate analysis was performed to predict the risk factors of BCG irrigated therapy failure. Result:By June 15, 2020, the median follow-up duration was 22.1 months(12.1, 32.3), and there was no statistical difference between the groups ( P=0.9024). There were 274 patients enrolled in BCG19 group, 277 patients enrolled in BCG15 group and 130 patients enrolled in the epirubicin group. The drop-off rate was 16.6%(113 cases)and made no difference between groups( P=0.6222). There were no significant difference in age, gender, BMI, or ECOG score( P>0.05). During the follow-up, 116 cases was detected recurrence or progression. The recurrence rate of the three groups was 14.2% and 14.8% in BCG19 group and BCG15 group, and 27.7% in the epirubicin group. There was no difference in recurrence rate between BCG19 and BCG15 group( P=0.9464). The recurrence rate of BCG19 group was lower than that of the epirubicin group ( P=0.0017). The recurrence rate of BCG15 group was lower than that of the epirubicin group ( P=0.0020). There was no difference in the cumulative recurrence free survival rate between BCG19 and BCG15 group (95% CI0.57-1.46, P=0.7173). The cumulative recurrence free survival rate of BCG 19 group was better than that of the epirubicin group( HR=0.439, 95% CI0.26-0.74, P=0.0006), and the cumulative recurrence free survival rate of BCG15 group was better than that of the epirubicin group ( HR=0.448, 95% CI0.29-0.80, P=0.0021). The total incidence of adverse events in 19 BCG19, BCG15 and epirubicin group were 74.5%, 72.6% and 69.8% respectively. There was no difference in the incidence of adverse events between BCG19 and BCG15 group( P=0.6153). The incidence of adverse events in epirubicin group was lower than that of BCG19( P=0.0051) and BCG15( P=0.0167) groups.There was no significant difference in the incidence of serious adverse events (SAE) among the three groups ( P=0.5064). Log rank test univariate analysis and Cox risk regression model multivariate analysis showed that the history of bladder cancer recurrence( HR=6.397, 95% CI1.95-20.94, P=0.0001)was independent risk factor for BCG irrigation failure. Conclusions:The 2 years’ efficacy of intravesical instillation of domestic BCG is better than than of epirubicin with good tolerance and safety. There is no difference between BCG19 and BCG15 group. BCG doesn’t increase SAE compared with epirubicin. Recurrence status was an independent prognostic factor regarding recurrence-free survival.